Oliver Kummer

Comparison of the dissolution and pharmacokinetic profiles of two galenical formulations of the endothelin receptor antagonist macitentan

Macitentan (ACT-064992) is an orally active endothelin receptor antagonist. We first compared the in vitro dissolution characteristics of uncoated and film-coated tablets with hard gelatin capsules containing 10mg ACT-064992. Subsequently, we compared the oral pharmacokinetics of ACT-064992 and its active metabolite ACT-132577 of the coated tablet and the gelatin capsule formulation in 11 male volunteers. The dissolution profile showed a rapid disintegration of all formulations with >90% dissolution of ACT-064992 within 45 min. The pharmacokinetics of ACT-064992 and its metabolite ACT-132577 were comparable for the two formulations. ACT-064992 revealed a slow absorption (median t(max) 8h) and a terminal half-life of approximately 13 h. Bioequivalence criteria were met for AUC(0-t) and AUC(0-infinity). Mean C(max) was 19% lower after ingestion of the tablet compared to capsules with its lower 90% confidence limit below the accepted bioequivalence range. The pharmacokinetics of the metabolite ACT-132577, characterized by a t(max) of approximately 48 h and a terminal half-life of approximately 45 h, was not different between the two formulations. We conclude that the absorption profile of the tablet differs from the capsule in peak but not in total exposure, which is not expected to be of clinical significance.

Pharmacokinetics of midazolam and metabolites in a patient with refractory status epilepticus treated with extraordinary doses of midazolam

The authors present a patient with refractory epilepsy who was treated with very high doses (up to 4 mg/min) of intravenous midazolam, phenytoin, carbamazepine, and other antiepileptics. Because it was known from the literature that the half-life of midazolam can increase at high dosage, the kinetics of midazolam (MDZ), 1′-hydroxymidazolam, and 4-hydroxymidazolam were assessed at steady state (dosage 1 mg/min) and after stopping treatment. Total body clearance of MDZ (33 L/kg) and intrinsic hepatic clearance (19 mL/min/kg) at steady state were both five to 10 times higher than after normal therapeutic doses, demonstrating hepatic cytochrome (CYP) 3A induction. Despite the high body clearance, the half-life of MDZ was in the range of 24 hours, approximately 10 times higher than after normal therapeutic doses. The volume of distribution at steady state was 33 L/kg, approximately 50 times higher than after normal therapeutic doses. The free fraction of MDZ was 58% at steady state, much higher than the 3% to 6% at normal therapeutic doses. The kinetics of intravenous MDZ is strongly dependent on its dose and on hepatic CYP3A activity. Even in patients with hepatic CYP3A induction, the half-life of MDZ increases with high doses as a result of a rise in its volume of distribution, which is a consequence of an increase in the free fraction of MDZ.

Acute Liver Failure in Two Patients with Regular Alcohol Consumption Ingesting Paracetamol at Therapeutic Dosage

Background: The possible role of alcohol in the development of hepatotoxicity associated with therapeutic doses of paracetamol (acetaminophen) is currently debated. Case Report: We describe 2 patients who were regular consumers of alcohol and who developed liver failure within 3–5 days after hospitalization and stopping alcohol consumption while being treated with 4 g paracetamol/day. A paracetamol serum level obtained in one of these patients was not in the toxic range. Possible risk factors for the development of hepatotoxicity in patients treated with therapeutic doses of paracetamol are discussed. Conclusion: In patients with risk factors, e.g. regular consumption of alcohol, liver failure is possible when therapeutic doses are ingested. We propose that the paracetamol dose should not exceed 2 g/day in such patients and that their liver function should be monitored closely while being treated with paracetamol.

Pharmacokinetics and Pharmacodynamics of Quetiapine in a Patient with a Massive Overdose

We present a case of massive overdose with the atypical antipsychotic quetiapine in a 34-year-old woman (body weight 65 kg). At admission, approximately 2 to 4 hours after ingestion of approximately 24 g of quetiapine, the patient was comatose (Glasgow Coma Scale score 5), requiring orotracheal intubation and transfer to the intensive care unit. Because of myoclonic jerks and generalized seizures, benzodiazepines were administered. In addition to transient mild hypotension after intubation, the main cardiovascular manifestation was sinus tachycardia. The QT interval was normal, and the QTc interval (Bazetts correction) was maximally prolonged to 620 ms. However, no malignant arrhythmias were observed. The patient recovered within 2 days but remained agitated and aggressive, for which she was transferred to the psychiatric clinic. The pharmacokinetics of quetiapine in such a large overdose could not be described by simple first-order kinetics. The initially observed rapid decline of the plasma concentrations of quetiapine could be simulated by first-order kinetics (half life = 4.1 hr) and can most probably be explained by rapid distribution into tissues. The final elimination of the drug from the body occurred after approximately 34 hours at much slower rate, most probably reflecting redistribution from tissues into blood and consecutive hepatic clearance of the drug.

Pharmacokinetics and pharmacodynamics of sildenafil in a patient treated with human immunodeficiency virus protease inhibitors.

We describe a 44-year-old male patient with human immunodeficiency virus (HIV) infection and pulmonary arterial hypertension who was treated with several protease inhibitors and with sildenafil. In order to guide treatment with sildenafil, the pharmacokinetics and dynamics of sildenafil were monitored at various time points. In comparison with healthy subjects, the maximal concentration in plasma (Cmax), area under the curve (AUC), and elimination half-life of sildenafil were approximately doubled in the patient. After increasing the sildenafil dose to ensure therapeutic drug levels over 24 hours, the pulmonary arterial hypertension and physical performance of the patient improved significantly. We conclude that the elimination of sildenafil is impaired in patients treated with protease inhibitors, but to a lesser extent than predicted from single-dose studies reported in the literature. Patients treated concomitantly with protease inhibitors and sildenafil need close monitoring of plasma levels, pharmacodynamics, and toxicity of sildenafil in order to be treated optimally.

Time controlled pulsatile transdermal delivery of nicotine: A phase I feasibility trial in male smokers

Nicotine substitution is a mainstay component in smoking cessation schemes. Current products including patches are poorly effective mainly because they do not give smokers the same pharmacokinetic profile of nicotine as cigarette consumption. This work evaluates a new computer operated delivery system for time controlled pulsatile transdermal administration of nicotine in a phase I clinical trial with twelve heavy smoking male volunteers. The device was affixed to the ventral side of the leading lower arm of the subjects and was programmed to deliver two pulses of drug within 16h with three delivery rates in a consecutive dose escalation study. Tolerability of the three increasing doses of nicotine was established. Plasma concentration of nicotine exhibited two peaks and one trough and reached therapeutically effective levels that behaved linearly with the drug load concentration of the device. In vivo input rate, delivered amount and elimination kinetics were deduced by pharmacokinetic modeling to analyze device performance. Timing, dose and duration of delivery were controlled by system operation parameters. Hence, feasibility of controlled pulsatile delivery of nicotine at predetermined intervals was demonstrated. After additional optimization, preprogrammed or on demand administration to meet individualized and circadian replacement needs should improve smoking cessation efficacy.

Reduction of hyperbilirubinemia with hypericum extract (St. John's Wort) in a patient with Crigler-Najjar syndrome type II.

Crigler‐Najjar syndrome (CN) type II is a congenital disease with unconjugated hyperbilirubinemia due to a deficiency of uridine 5′‐diphospho‐glucuronosyltransferase 1A1. Since the currently proposed treatment with phenobarbital is associated with adverse reactions, we investigated the effect of hypericum extract.

Reduction of hyperbilirubinemia with hypericum extract in a patient with Crigler‐Najjar syndrome type II

Crigler‐Najjar syndrome (CN) type II is a congenital disease with unconjugated hyperbilirubinemia due to a deficiency of uridine 5′‐diphospho‐glucuronosyltransferase 1A1. Since the currently proposed treatment with phenobarbital is associated with adverse reactions, we investigated the effect of hypericum extract.